Anaesthesia may generally be described as a state in which noxious events such as surgical procedures are rendered imperceptible by the body, the state being accompanied either by loss of consciousness (general anaesthesia) or no loss of consciousness (local anaesthesia). A complete or general anaesthetic given by inhalation or intravenous route produces a state of profound sleep and loss of motor activity (hypnosis), analgesia, muscle relaxation and protection against the increase in blood pressure and heart rate resulting from surgical stress. Anaesthetics generally display hypometabolic activity and frequently act as respiratory or cardiovascular depressants. Certain anaesthetics may be used to produce deliberate hypotensive effects which are very valuable in intracranial and other surgical procedures. Although a large number of agents having anaesthetic and cardiovascular activity have been identified and/or commercialised, there is a continuing need for now materials having hypometabolic activity, which are valuable for inducing sleep, reduction in motor activity, hypotension, bradycardiac, hypocoagulative, anti-aggregant and other hypobiosis effects such as reduced oxygen consumption and reduced body temperature, which would be valuable for use in complex surgical procedures or in the treatment of life threatening and/or traumatic situations such as brain stroke and myocardial infarction, and which have excellent potency, duration and CNS and cardiovascular toxicity profiles with absence of side effects such as tremor, convulsions and irregular breathing and heart beat.
There is considerable body of data concerning 6-R-1,3,4-thiadiazin-2-amines (for reviews see [1-3]). Also patent literature provides data on myo-relaxant [4-7], sedative [8,9], spasmolytic [10-12] and other types of biological activity [3]. A number of 5-aryl derivatives of 1,3,4-thiadiazines have been specifically described in the art [14-20] as well as 6-alkyl and 6-phenyl analogs thereof [13 and 21]. The value of 6-R-1,3,4-thiadiazin-2-amines as hypometabolic anaesthetics and cardiovascular agents has not hitherto been recognised however. Moreover, many of the5e compounds are apparently novel and have not been previously described in the literature.
The prior art on 6-R-1,3,4-thiadiazin-2-amines includes:
1. H. Beyer, Z. Chem., Bd.9, S. 361, (1969). PA0 2. S. V. Usoltseva, G. P. Andronnikova, and V. S. Mokrushin, khim. Geterotsikl. Soedin., No 4, 435, (1991). PA0 3. A. P. Novikova, N. M. Perova, and O. N. Chupaichin, Khim. Goereotsikl. Soedin., No 11, 1443, (1991). PA0 4. W. D. Jones and F. P. Miller. US-A-4,309,426 (1982). PA0 5. W. D. Jones and F. P Miller. BE-A-884,991 (1980). PA0 6. W. D. Jones and F. P. Miller. DE-A-3,042,295 (1982). PA0 7. FR-A-2,493,844 (1982). PA0 8. US-A-4,272,532 (1982). PA0 9. F. P. Miller and W. D. Jones. BE-A-884,990 (1980). PA0 10. W. D. Jones and F. P. Miller. DE-A-3,031,703 (1981). PA0 11. Fisons PLC, Japan Kokai, Toroyo Koho JP-A-6253976. PA0 12. W. D. Pfeiffer and E. Bulka, DD-A-220311 (1985). PA0 13. N. Yoshida, K. Tranaka, and Y. Iizuk. Japan Kokai 7438839 (1974). PA0 14. L. N. Pasina, O.N. Chupakhin and M. V. Chibiryak. Radiobiologiya, 30(2), 162-165 (1990). PA0 15. A. V. Belik et al, Khjim.-Farmi. Zh., 26(3), 62-64 (1992). PA0 16. N. M. Perova et al, Kchim. Geterotsikl. Soedin., No 4, 565-566 (1993). PA0 17. E Bulka and W. D. Pfeiffer. DD-A-289824. PA0 18. W. D. Pfeiffer and E Bulka, Synthesis, No 7, 485-486 (1977). PA0 19. T Werner et al, US-A-4,940,790 (1990). PA0 20. A. P. Novikova et al1, SU-A-1726478. PA0 21. E Bulka et al, DD-A-228248.